Much effort has been devoted to the study of a discrete group of breathing disorders that occur primarily during sleep with consequences that may persist throughout the waking hours in the form of daytime sleepiness, and result in substantial economic loss (e.g., thousands of lost man-hours) or cause employment safety issues (e.g., employee non-attentiveness during operation of heavy-machinery). Sleep-related breathing disorders are characterized by repetitive reduction in breathing (hypopnea), periodic cessation of breathing (apnea), or a continuous or sustained reduction in ventilation.
In general, sleep apnea is defined as an intermittent cessation of airflow at the nose and mouth during sleep. By convention, apneas of at least 10 seconds in duration have been considered important; however, in most individuals, apneas are 20-30 seconds in duration and may be as long as 2-3 minutes. While there is some uncertainty as to the minimum number of apneas that should be considered clinically important, by the time most individuals come to a doctor's attention they have at least 10 to 15 events per hour of sleep.
Sleep apneas have been classified into three types: central, obstructive (the most common type), and mixed. In central sleep apnea, the neural drive to all respiratory muscles is transiently abolished. In obstructive sleep apneas, airflow ceases despite continuing respiratory drive because of occlusion of the oropharyngeal airway. Mixed apneas, which consist of a central apnea followed by an obstructive component, are a variant of obstructive sleep apnea.
Obstructive sleep apnea syndrome (OSAS) has been identified in as many as 24% of working adult men and 9% of similar women, with peak prevalence in the sixth decade. Habitual heavy snoring, which is an almost invariant feature of OSAS, has been described in up to 24% of middle-aged men, and 14% of similarly aged women, with even greater prevalence in older subjects. A definitive event of obstructive sleep apnea syndrome is the occlusion of the upper airway, frequently at the level of the oropharynx. The resultant apnea generally leads to a progressive-type asphyxia until the individual is briefly aroused from the sleeping state, thereby restoring airway patency and airflow.
The recurrent episodes of nocturnal asphyxia and of arousal from sleep that characterize OSAS lead to a series of secondary physiologic events, which in turn give rise to the clinical complications of the syndrome. The most common manifestations are neuropsychiatric and behavioral disturbances that are thought to arise from the fragmentation of sleep and loss of slow-wave sleep induced by the recurrent arousal responses. Nocturnal cerebral hypoxia also may play an important role. The most pervasive manifestation is excessive daytime sleepiness. OSAS is now recognized as a leading cause of daytime sleepiness and has been implicated as an important risk factor for such problems as motor vehicle accidents. Other related symptoms include, but are not limited to, intellectual impairment, memory loss, personality disturbances, and impotence.
The other major manifestations are cardiorespiratory in nature and are thought to arise from the recurrent episodes of nocturnal asphyxia. Most individuals demonstrate a cyclical slowing of the heart during the apneas to 30 to 50 beats per minute, followed by tachycardia of 90 to 120 beats per minute during the ventilatory phase. A small number of individuals develop severe bradycardia with asystoles of 8 to 12 seconds in duration or dangerous tachyarrhythmias, including unsustained ventricular tachycardia. OSAS also aggravates left ventricular failure in patients with underlying heart disease. This complication is most likely due to the combined effects of increased left ventricular afterload during each obstructive event, secondary to increased negative intrathoracic pressure, recurrent nocturnal hypoxemia, and chronically elevated sympathoadrenal activity.
Central sleep apnea is less prevalent as a syndrome than OSAS, but can be identified in a wide spectrum of patients with medical, neurological, and/or neuromuscular disorders associated with diurnal alveolar hypoventilation or periodic breathing. A definitive event in central sleep apnea is transient abolition of central drive to the ventilatory muscles. The resulting apnea leads to a primary sequence of events similar to those of OSAS. Several underlying mechanisms can result in cessation of respiratory drive during sleep. Defects in the metabolic respiratory control system and respiratory neuromuscular apparatus are apparent. Other central sleep apnea disorders arise from transient instabilities in an otherwise intact respiratory control system. In individuals with clinically significant central sleep apnea, the primary sequence of events that characterize the disorder leads to prominent physiological and clinical consequences. In those individuals with central sleep apnea alveolar hypoventilation syndrome, daytime hypercapnia and hypoxemia are usually evident and the clinical picture is dominated by a history of recurrent respiratory failure, polycythemia, pulmonary hypertension, and right-sided heart failure. Complaints of sleeping poorly, morning headache, and daytime fatigue and sleepiness are also prominent. In contrast, in individuals whose central sleep apnea results from an instability in respiratory drive, the clinical picture is dominated by features related to sleep disturbance, including recurrent nocturnal awakenings, morning fatigue, and daytime sleepiness.
Currently, the most common and most effective treatment for adults with sleep apnea and other sleep-related breathing disorders are mechanical forms of therapy that deliver positive airway pressure (PAP). Under PAP treatment, an individual wears a tight-fitting plastic mask over the nose when sleeping. The mask is attached to a compressor, which forces air into the nose creating a positive pressure within the patient's airways. The principle of the method is that pressurizing the airways provides a mechanical “splinting” action that prevents airway collapse and therefore, obstructive sleep apnea. Although an effective therapeutic response is observed in most patients who undergo PAP treatment, many patients cannot tolerate the apparatus or pressure and refuse treatment. Moreover, covert monitoring studies clearly demonstrate that long-term compliance with PAP treatment is very poor.
A variety of upper airway and craniofacial surgical procedures have been attempted for treatment of OSAS. While adenotonsillectomy appears to be an effective cure for OSAS in many children, upper airway surgery is rarely curative in adult OSAS patients. Surgical success is generally taken to be a 50% reduction in apnea incidence and there are no useful screening methods to identify the individuals that would benefit from the surgery versus those who would not derive a benefit.
Pharmacological treatments of several types have been attempted in patients with sleep apnea but, thus far, none have proven to be generally useful. (see Smith & Quinnell (2004) Drugs 64:138-1399). A number of compounds have been tested because of their expected respiratory stimulant properties. These include acetazolamide, a carbonic anhydrase inhibitor that produced variable improvement in individuals with primarily central apneas, but caused an increase in obstructive apneas; medroxyprogesterone, a progestin that has demonstrated no consistent benefit in OSAS; and theophylline, a compound usually used for the treatment of asthma that may benefit patients with central apnea, but appears to be of no use in adult patients with obstructive apnea.
Other attempted pharmacological treatments include administration of adenosine, adenosine analogs and adenosine reuptake inhibitors (see, e.g., U.S. Pat. No. 5,075,290). Specifically, adenosine, a ubiquitous compound within the body that is elevated in individuals with OSAS, has been shown to stimulate respiration and is somewhat effective in reducing apnea in an animal model of sleep apnea.
Other agents for treating OSAS include compounds that stimulate brain activity or are opioid antagonists. Specifically, since increased cerebral spinal fluid opioid activity has been identified in OSAS, central stimulants or opioid antagonists are thought to be a helpful treatment of OSAS. However, doxapram, a compound that stimulates the central nervous system and carotid body chemoreceptors, while decreasing the length of apneas, does not alter the average arterial oxygen saturation in individuals with obstructive sleep apnea. Further, the opioid antagonist naloxone, which is known to stimulate ventilation, is only slightly helpful in individuals with obstructive sleep apnea.
Several agents that act on neurotransmitters and neurotransmitter systems involved in respiration have been tested in individuals with OSAS. Most of these compounds have been developed as anti-depressant medications that work by increasing the activity of monoamine neurotransmitters, including norepinephrine, dopamine, and serotonin. For example, protriptyline, a tricyclic antidepressant, has been tested in several small trials with variable results and frequent and significant side effects. As serotonin may promote sleep and stimulate respiration, tryptophan, a serotonin precursor, as well as selective serotonin reuptake inhibitors (SSRIs) have been tested in individuals with OSAS. Although the serotonin reuptake inhibitor, fluoxetine has been suggested for treating sleep apnea (U.S. Pat. No. 5,356,934), initial evidence suggests that such compounds may yield measurable benefits in only approximately 50% of individuals with OSAS. The rationale for using SSRIs such as fluoxetine or paroxetine to treat sleep apnea syndrome rests in part on their ability to stimulate upper airway motor outputs. Applications of serotonin to the floor of the fourth ventricle (Rose, et al. (1995) Respir. Physiol. 101:59-69) or into the hypoglossal motor nucleus (Kubin, et al. (1992) Neurosci. Lett. 139:243-248) produced upper airway motor activation in cats; effects that appear to be mediated predominantly by serotonin subtype 2 receptors (Okabe, et al. (1997) Respir. Physiol. 110:151-160; Volgin, et al. (2003) Eur. J. Neurosci. 17:1179-1188). Conversely, systemic administration of 5-hydroxytryptamine 2 receptor antagonists to English bulldogs reduced electrical activation of upper airway muscles, diminishing upper airway cross-sectional area (Veasey, et al. (1996) Am. J. Respir. Crit. Care Med. 153:776-786). These observations provide a likely explanation for the improvements in sleep-disordered breathing observed in some patients following SSRI treatment, but illustrate that to be generally effective, SSRI treatment must be combined with another agent.
Buspirone, a specific serotonin subtype 1 receptor agonist that stimulates respiration (Mendelson, et al. (1990) Am. Rev. Respir. Dis. 141:1527-1530), has been shown to reduce apnea index in 4 of 5 patients with sleep apnea syndrome (Mendelson, et al. (1991) J. Clin. Psychopharmacol. 11:71-72) and to eliminate post-surgical apneustic breathing in one child (Wilken, et al. (1997) J. Pediatr. 130:89-94). The use of serotonin agonists to treat apneas has been suggested in U.S. Pat. Nos. 6,552,062; 6,433,175; 6,432,956; 6,387,907; 6,356,598; 6,380,238; and 6,303,608.
Serotonin antagonists also have been examined as drug treatments for sleep apnea in humans and in animal models of sleep-related breathing disorders. In rats that express frequent central apneas during all sleep stages, the serotonin antagonists ondansetron, R-zacopride, and mirtazapine all have been shown to reduce apnea frequency. Mirtazapine was able to reduce apnea frequency by 50% in one study of OSAS patients, whereas ondansetron failed to demonstrate any effect in another study. Nevertheless, the use of serotonin antagonists to treat OSAS has been disclosed in U.S. Pat. Nos. 6,835,740; 6,727,242; 6,649,183; 6,613,779; 6,576,670; 6,559,165; 6,552,062; 6,548,082; 6,465,490; 6,331,536; 6,303,595; 6,277,864; 6,143,792; 6,048,879; 5,995,470 and U.S. patent application Ser. No. 10/285,277.
Several other treatments for sleep apnea have been disclosed, including the administration of the nucleoside uptake blocker dipyridamole (U.S. Pat. No. 5,502,067), pilocarpine compounds (U.S. Pat. No. 5,407,953), ubidecarenone (U.S. Pat. No. 5,422,374), somatostatin receptor agonists (U.S. patent application Ser. No. 10/280,517), and acetylcholine-esterase inhibitors (U.S. Pat. No. 6,034,117). Stimulation of various structures, such as the pontine intertrigeminal region (Radulovacki, et al. (2003) Brain Research 975:66-72; Radulovacki, et al. (2004) Sleep 27:383-387) and the pedunculopontine tegmentum (Saponjic, et al. (2003) Resp. Physiol. Neurobiol. 138:223-237) by the excitatory amino acid glutamate has been shown to evoke immediate apnea, and a glutamate release inhibitor was shown to reduce the frequency of central apneas in a rat model (Radulovacki, et al. (2001) J. Pharm. Pharmacol. 53:1555-9). The use of glutamate antagonists or release inhibitors to treat OSAS is disclosed in U.S. Pat. No. 6,555,564. In addition, the cannabinoid receptor agonist Δ9-tetrahydrocannibinol has been shown to reduce sleep apneas in an animal model (Carley, et al. (2002) Sleep 25:391-398; U.S. patent application Ser. No. 10/472,136).
In view of the fact that the only viable treatment for individuals suffering from sleep-related breathing disorders is a mechanical form of therapy for which patient compliance is low, and that hopes for pharmacological treatments have yet to come to fruition, there remains a need for pharmacologically-based treatments that would offer benefits to a broad base of individuals suffering from a range of sleep-related breathing disorders. There also remains a need for a viable treatment of sleep-related breathing disorders that would have a high rate of patient compliance. The present invention meets this need in the art.